2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia.

Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.

Effect of liraglutide therapy on serum fetuin A in patients with type 2 diabetes and non-alcoholic fatty liver disease.

OBJECTIVE: We aimed to compare the effectiveness of liraglutide vs. pioglitazone on hepatic fat content and serum fetuin A levels in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. METHODS: This was a single-center, open-label, prospective, and randomized trial using a parallel design and lasting 24 weeks. Sixty patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease were randomly assigned to the liraglutide and pioglitazone groups on a 1:1 basis using a computer-generated sequence. Fetuin-A levels were determined using enzyme-linked immunosorbent assay. Hepatic fat content was measured using proton 1H-MRS on a 1.5T whole-body MRI scanner. All analyses were performed with SPSS version 13.0. RESULTS: In the liraglutide group, fetuin-A levels decreased after 24 weeks (666.1±109.4 vs. 443.7±90.5µg/mL, P<0.05). In the pioglitazone group, fetuin-A levels also decreased after 24 weeks (659.3±111.8 vs. 538.1± 101.0µg/mL, P<0.05) but not to the level of the liraglutide group. The liraglutide treatment resulted in a decrease in 1H-MRS (24.1±3.0 vs. 20.1±3.8, P<0.05). After 24 weeks, ΔFetuin-A was positively correlated with Δweight (r=0.756, P=0.035), ΔBMI (r=0.653, P=0.006), Δwaist circumference (r=0.767, P=0.010), and Δ1H-MRS (r=0.732, P=0.004) in the liraglutide group. CONCLUSIONS: Liraglutide treatment resulted in a decrease in hepatic fat content and fetuin-A compared with pioglitazone treatment in patients with T2DM and NAFLD. Fetuin-A is positively correlated with weight and hepatic fat content. The reduction in the hepatic fat content may be attributed to weight loss rather than reduction of glucose.